tbuckley/cabot-search huggingface dataset:
Effect of neutrophil extracellular traps on tumor lymph nodes.
Authors: Xin SU, Ariane Brassard, Iqraa Dhoparee-Doomah, Ramin Rohanizadeh, Betty Giannias, France Bourdeau, Veena Sangwan, Roni Rayes, Jonathan Spicer, Lorenzo Ferri, Jonathan Cools-Lartigue
Journal: Journal of Clinical Oncology (2022)

4033 Background: In most human cancers, regional lymph nodes (LNs) are the first sites of metastasis. In addition to being an important part of the tumor staging system, with the advent of novel therapies, lymph node metastasis has become a crucial clinical intervention point before distant metastasis, the leading cause of cancer-associated deaths. To initiate metastasis, the conditions of LNs need to be optimized for tumor cell deposition and growth. This process is believed to be mediated by the activation of immune cells including polymorphonuclear neutrophils (PMNs). However, the cellular mechanism is not well defined. Our early observations suggest that PMNs and neutrophil extracellular traps (NETs), DNA comprising structures that are extruded in response to inflammatory cues, are associated with adverse oncologic outcomes. Thus, one potential mechanism of increased LN metastasis is that tEVs recruit PMNs and propend NETs formation. Methods: Human tissue micro-arrays (TMAs) of gastroesophageal (GEA) cancer patients were stained with PMN and NETs markers and quantified by HALO software. C57BL/6 or pad4-/- mice were injected with B16F10 or H59 cells alone or treated with neutrophil elastase inhibitor (NEi) or PMN depletion antibody. LN sections were stained with NETs markers and quantified by ImageJ (NIH). Results: In the study of 175 GEA cancer patients, lymphatic NET deposition was observed in both tumor infiltrated lymph nodes and tumor negative lymph nodes. We also demonstrated high LN NETs deposition was associated with reduced survival, even in the absence of overt metastasis ( p=0.03). Next, we sought to investigate the dynamic and the consequence of LN NETs deposition using animal models. We found that LN Neutrophil Recruitment and NET deposition happens in a pre-metastatic manner. Moreover, LN metastasis was abrogated through different kinds of NETs inhibition (neutrophil depletion, pad4 knockout and NEi treatment, n=10, p&lt;0.001), demonstrating the consequences of LN NETs deposition and its potential as a treatment target. Finally, we showed that the LN PMN recruitment and NETs formation was mediated by increased production of IL-8 by Lymphatic Endothelial Cells (LEC). Conclusions: Together, we demonstrated that NETs can contribute to LN metastasis, and can serve as a potential therapeutic targets. By further investigating the detailed mechanism, this project will lead to major advances in the management of cancer patients.
Safety monitoring practice during the initiation of tyrosine kinase inhibitors (TKIs) for NSCLC treatment.
Authors: Avani Singh, Rafael Rubiera Pepe, Michael Rahman Shafique, James Kevin Hicks, Tawee Tanvetyanon
Journal: Journal of Clinical Oncology (2022)

e21090 Background: TKIs are standard treatment for non-small cell lung cancer (NSCLC) which harbors an actionable mutation. TKIs have a unique toxicity profile, distinct from conventional chemotherapy. Although the manufacturer of each TKI often issues a specific safety precaution on its label, no set schedule has been widely adopted. We surveyed the safety monitoring practice at a large academic institution. Methods: Electronic medical records of patients with ROS1, ALK or EGFR-mutated NSCLC who began a TKI during 2017-2021 were retrospectively reviewed. For each patient, the observation period started from the date of TKI prescription and lasted through day 60. Safety metrics were formulated based on drug label recommendations of each TKI. For each treatment course, the occurrence of 2 index safety monitoring activities (Table) were recorded. Results: Analysis included 130 treatment courses: 82 osimertinib, 20 alectinib, 15 crizotinib and 13 lorlatinib. Median age was 64.3 years, with 66% female, 81% white, 91% ECOG 0/1, 28% zero comorbidity, and 99% non-smoker. For osimertinib, EKG was obtained at baseline (within 30 days of treatment initiation) in 69.5% of observations, and LVEF, in 26.8%. By 60 days, these numbers barely increased (Table). Overall, absence of any index safety monitoring activity occurred in 41 of 130 (32%) treatment courses. Multivariable logistic regression analysis found a trend toward less monitoring among non-white patients: Odds ratio 0.35 (95% CI 0.11-1.09, p = 0.07). No association was found between the number of cardiac risk factors and LVEF monitoring or the use of QT prolonging medication and QTc monitoring. Conclusions: We observed a wide variation in the safety monitoring practice during TKI initiation. Deviation from the manufacturer recommendation was most pronounced for CPK monitoring in alectinib. Future study is needed to define the clinical significance of deviation and to identify barriers to safety monitoring.[Table: see text]
Non-cytotoxic nanoparticles re-educating macrophages achieving both innate and adaptive immune responses for tumor therapy
Authors: Shengmei Wang, Xuanjun Liu, Minghua Yang, Linqi Ouyang, Jinsong Ding, Shengfeng Wang, Wenhu Zhou
Journal: Asian Journal of Pharmaceutical Sciences (2022)

Macrophages are important antigen-presenting cells to combat tumor via both innate and adaptive immunity, while they are programmed to M2 phenotype in established tumors and instead promote cancer development and metastasis. Here, we develop a nanomedicine that can re-educate M2 polarized macrophages to restore their anti-tumor activities. The nanomedicine has a core-shell structure to co-load IPI549, a PI3Kγ inhibitor, and CpG, a Toll-like receptor 9 agonist. Specifically, the hydrophobic IPI549 is self-assembled into a pure drug nano-core, while MOF shell layer is coated for CpG encapsulation, achieving extra-high total drugs loading of 44%. Such nanosystem could facilitate intracellular delivery of the payloads but without any cytotoxicity, displaying excellent biocompatibility. After entering macrophages, the released IPI549 and CpG exert a synergistic effect to switch macrophages from M2 to M1 phenotype, which enables anti-tumor activities via directly engulfing tumor cells or excreting tumor killing cytokines. Moreover, tumor antigens released from the dying tumor cells could be effectively presented by the re-educated macrophages owing to the up-regulation of various antigen presenting mediators, resulting in infiltration and activation of cytotoxic T lymphocytes. As a result, the nanosystem triggers a robust anti-tumor immune response in combination with PD-L1 antibody to inhibit tumor growth and metastasis. This work provides a non-cytotoxic nanomedicine to modulate tumor immune microenvironment by reprograming macrophages.
Efficacy and safety of sintilimab plus XELOX as neoadjuvant therapy in patients with locally advanced gastric cancer: A single-arm open-label phase II trial.
Authors: Honghai Guo, Ping'an Ding, Peigang Yang, Yuan Tian, Yang Liu, Ze Zhang, Tao Zheng, Zhidong Zhang, Dong Wang, Bibo Tan, Xuefeng Zhao, Yong Li, Qun Zhao
Journal: Journal of Clinical Oncology (2022)

e16091 Background: Neoadjuvant chemotherapies have been widely recommended by clinical guidelines for patients with locally advanced gastric cancer. However, the evidence of combining neoadjuvant chemotherapy with anti-programmed death 1 (anti-PD-1) antibody therapy for patients with locally advanced gastric cancer is inadequate. Thus, we conducted a single-arm phase II trial to evaluate the efficacy and safety of anti-PD-1 antibody sintilimab and XELOX regimen (capecitabine plus oxaliplatin) in patients with locally advanced gastric adenocarcinoma. Methods: Patients with locally advanced(cT3-4 N+ M0, CY0,P0) were enrolled and received four preoperative cycles of XELOX (oxaliplatin 130mg/m 2 , IV, d1 with capecitabine 1000mg/m 2 , bid, d1-d14, q21d) and sintilimab (200mg, IV, q21d). Surgery was performed within 3-4 weeks after completion preoperative therapy. After surgery, patients received four cycles of XELOX. The primary endpoint was the pathological complete response (pCR) rate and the secondary endpoints were major pathologic response (MPR) rate, R0 resection rate, safety, disease-free survival (DFS) and overall survival (OS). This clinical trial is registered at ChiCTR.gov.cn: ChiCTR2000030414. Results: From March 2020 to July 2021, 30 patients were enrolled, with median age 62 years (range30-72), males 18, cT3/T4: 8/22, cN1/2/3: 10/14/6, intestinal diffuse type (Lauren classification):17/13, ECOG PS 0/1/2: 19/8/3. There were 19(63.3%) patients with PD-L1 CPS≥1. All patients were available for preoperative response evaluation, the objective response (ORR) rate was 70.0% (95% CI, 50.6%-85.3%) and the disease control (DCR) rate was 100% (95% CI, 88.4%-100%). All (100%) achieved R0 resection. 10 patients (33.3%) achieved pCR (TRG 0) and 19 patients (63.3%) had MPR (TRG 0-1). Common treatment-related adverse events (TRAEs) were anemia (36.7%), leukopenia (36.7%), neutropenia (30.0%), diarrhea (26.6%), ALT increase (23.3%), AST increase (13.3%), thrombocytopenia (10.0%), vomiting (10.0%). The potential immune-related adverse events (irAEs) were dermatitis (6.7%), hypothyroidism (3.3%), pneumonia (10.0%). Most of the TRAEs and potential irAEs were grade 1 or 2. Grade3 TRAEs and irAEs included ALT increase (3.3%), AST increase (3.3%), dermatitis (3.3%). There were no severe complications and death related to the operation. The median postoperative hospital stay was 8 days (range6-23 days). Conclusions: Sintilimab plus XELOX as neoadjuvant therapy showed an encouraging pCR rate, MPR rate and manageable safety. This combination regimen might provide a new option for patients with locally advanced gastric cancer. Clinical trial information: ChiCTR2000030414.
Evaluation of cross-disciplinary educational material to improve patients’ knowledge and utilization of palliative radiation therapy.
Authors: Faryal Rizvi, Meredith Young, Muhammad Hamza Hamza Habib, Joshua Kra, Ankit Shah, Tina M. Mayer, Biren Saraiya, Malcolm David Mattes
Journal: Journal of Clinical Oncology (2022)

e24082 Background: Palliative radiation therapy (PRT) is underutilized in the United States, in part due to misconceptions among patients and other providers about its risks, benefits, and indications. Empowered patients, who are more knowledgeable about how radiation can alleviate cancer-induced symptoms, may facilitate more appropriate and timely use of PRT. In this pilot study patient-directed educational material describing PRT was developed and used among patients being treated in medical oncology and palliative care clinics. The hypothesis is that most patients will gain new knowledge from educational content about PRT, and perceive it as useful in their care. Materials/Methods: A 1-page educational handout was developed to convey general information about the purpose, logistics, benefits, risks, and common indications for PRT. Patients undergoing treatment for a metastatic solid tumor were invited to participate during their regular clinic visit. Patients who chose to participate read the handout, and then completed a multiple choice questionnaire assessing how much they learned from the handout (nothing vs. little vs. lots), whether the information in the handout was useful (no vs. somewhat vs. very), as well as other questions. Responses were anonymous. There was no follow-up with participants. Descriptive statistics are reported, with Fisher’s Exact Test used to compare subgroups of patients. Results: A total of 70 patients from 1 palliative care physician and 4 medical oncologists participated between June – December 2021. Sixty-five patients (89%) felt they learned from the handout (38% learned “lots”) and 69 (94.5%) felt the information was useful (53% “very useful”). Twenty-one patients (28.8%) learned that PRT can help with symptom relief, 55 (75%) learned that PRT can be delivered in a course of 5 treatments or less, and 43 patients (59%) learned that PRT usually has few side effects. Furthermore, 16 (22%) felt they currently had symptoms not being treated well enough, and 34 (47%) felt they currently had symptoms that radiation might help with. Most patients felt more comfortable bringing symptoms to a medical oncologist’s (n = 57, 78%) or radiation oncologist’s (n = 51, 70%) attention after reading the handout. Forty-one patients (56.2%) reported a prior visit with a radiation oncologist, but this did not impact their responses related to learning from the handout ( p&lt; 0.001) or finding the handout useful ( p&lt; 0.001). Conclusions: Patient-directed educational material about PRT provided outside of a radiation oncology department was perceived by patients as improving their knowledge, and adding value in their care, independent of their prior exposure to a radiation oncologist. Further research will evaluate the impact of the educational material on referral patterns.
SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic perturbations after recovery
Authors: Justin J. Frere, Randal A. Serafini, Kerri D. Pryce, Marianna Zazhytska, Kohei Oishi, Ilona Golynker, Maryline Panis, Jeffrey Zimering, Shu Horiuchi, Daisy A. Hoagland, Rasmus Møller, Anne Ruiz, Albana Kodra, Jonathan B. Overdevest, Peter D. Canoll, Alain C. Borczuk, Vasuretha Chandar, Yaron Bram, Robert Schwartz, Stavros Lomvardas, Venetia Zachariou, Benjamin R. tenOever
Journal: Science Translational Medicine (2022)

The host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in prolonged pathologies collectively referred to as post-acute sequalae of COVID-19 (PASC) or long COVID. To better understand the mechanism underlying long COVID biology, we compared the short- and long-term systemic responses in the golden hamster after either SARS-CoV-2 or influenza A virus (IAV) infection. Results demonstrated that SARS-CoV-2 exceeded IAV in its capacity to cause permanent injury to the lung and kidney and uniquely affected the olfactory bulb (OB) and olfactory epithelium (OE). Despite a lack of detectable infectious virus, the OB and OE demonstrated myeloid and T cell activation, proinflammatory cytokine production, and an interferon response that correlated with behavioral changes extending a month after viral clearance. These sustained transcriptional changes could also be corroborated from tissue isolated from individuals who recovered from COVID-19. These data highlight a molecular mechanism for persistent COVID-19 symptomology and provide a small animal model to explore future therapeutics.
A phase I study of gemcitabine/nab-paclitaxel/S-1 chemotherapy in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma.
Authors: Chen Chang, Xiaofen Li, Ke Cheng, Zhaolun Cai, Junjie Xiong, Wanrui Lv, Ruizhen Li, Pei Zhang, Dan Cao
Journal: Journal of Clinical Oncology (2022)

e16261 Background: Systemic chemotherapy is the primary treatment in patients with locally advanced or metastatic pancreatic ductal adenocarcinomas (PDAC). More effective treatment options are highly awaited . The aim of this study was to evaluate the toxicity and feasibility of triweekly gemcitabine/nab-paclitaxel/S-1 (GAS) chemotherapy in patients with locally advanced or metastatic PDAC, determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of S-1 in this regimen, and explore the preliminary efficacy. Methods: Eligible patients with locally advanced or metastatic PDAC received GAS chemotherapy on a 21-day cycle. Fixed-dose of nab-paclitaxel (125 mg/m 2 ) and gemcitabine (1000 mg/m 2 ) were given intravenously on days 1 and 8. Different doses of S-1 were given orally twice daily from day 1 to day 14 within a 3+3 dose escalation design. According to patients` body surface area, the dose-escalation design was as follows: patients with a body surface area of 1.25–1.5 m 2 received S-1 40 mg/d initially and the dose was increased to 60 mg or 80 mg. Patients with a body surface area of more than 1.5 m 2 received S-1 60 mg/d initially and the dose was increased to 80 mg or 100 mg. The primary endpoints were to evaluate the toxicity and determine the DLT and MTD of S-1. The secondary endpoint was to evaluate efficacy. Results: A total of 21 eligible patients were included. Due to the infrequence of patients with a body surface area of 1.25–1.5 m 2 , only 2 patients were included in cohort of S-1 40 mg. The dose-escalation for patients in this group failed to be enrolled completely. For patients with a body surface area of more than 1.5 m 2 , 3 DLTs in 7 patients were detected at cohort of S-1 100 mg (grade 3 thrombocytopenia with hemorrhage, grade 3 rash, and grade 3 mucositis/stomatitis). S-1 80 mg/d (body surface area: &gt; 1.5 m 2 ) was considered to be the MTD in GAS chemotherapy (21-day cycle). No grade 4 adverse events (AEs) or treatment-related deaths were observed. The most common occurring hematologic AE of any grade was anemia (38.1%). The most frequent nonhematologic AEs of any grade were peripheral neuropathy (38.1%), dyspepsia (23.8%), constipation (23.8%), and alopecia (23.8%). After 2 cycles of GAS chemotherapy, the objective response rate was 36.8% and the disease control rate was 94.7%. The median progression-free survival was 5.3 (95% CI, 4.6 to 6.0) months and the median overall survival was 10.3 (95% CI, 8.1 to 12.5) months. Conclusions: GAS chemotherapy (21-day cycle) with nab-paclitaxel 125 mg/m 2 , gemcitabine 1000 mg/m 2 , and S-1 80 mg/d (body surface area: &gt; 1.5 m 2 ) was detected with the acceptable toxicity and significant clinical control in patients with locally advanced or metastatic PDAC. It is valuable to conduct further phase II trials. Clinical trial information: ChiCTR1900027833.
Survivorship profile and post-treatment quality of life of oral cancer survivors in comparison with caregivers: An analysis of a real-world cohort of a developing country.
Authors: Abhinav Thaduri, Manu Malhotra, Pankaj Kumar Garg, Mahendra Pal Singh, Dharma Ram Poonia, Pankaj Sharma, Ravi Gupta, Manoj kumar Gupta
Journal: Journal of Clinical Oncology (2022)

e18036 Background: Oral cavity cancer is the second most common cancer in India; India bears the most burden of oral cancer in the world. The most effective way to study the effectiveness of treatments is in clinical trials, but the quality of life (QOL) and post-treatment effects of those treatments are seldom studied in real-world settings. Methods: All oral cancer survivors treated with curative intent at our institute from September 2019 to January 2021, who were disease-free for a minimum of six months following treatment, were included in this study. The QOL of these cancer survivors was compared with that of their caregivers using the WHOQOL BREF questionnaire. The complete survivorship profile was evaluated using a Constant shoulder score for shoulder dysfunction, clinical oral dryness score (CODS) for xerostomia, Sydney Swallow Questionnaire (SSQ) for swallowing dysfunction, Patterson scale for lymphedema, Comprehensive Score for financial Toxicity (COST)‐Functional Assessment of Chronic Illness Therapy (FACIT) questionnaire for financial toxicity, Depression, Anxiety and Stress Scale - 21 Items (DASS-21) for psychological wellbeing. Results: A total of seventy-nine survivors were included. The median age was 49 years. Though both survivors and caregivers had similar QOL scores in the physical and environmental domains, survivors had poor scores in the social (M = 58.7,SD = 21.9) and psychological domains (M = 60.4,SD = 15.6). The T stage (p = 0.06), surgery (p = 0.008), and trismus (p = 0.03) were significant factors affecting swallowing. Those patients who had undergone selective neck dissection had better shoulder scores compared to those who had modified radical neck dissection (p = 0.006). 75% of people had xerostomia and 10.9% had severe xerostomia. Internal lymphedema was seen in 30.4% of people. Depression and anxiety were recorded in 46 (58.2%) and 33 (41.8%) patients respectively. Employment status (p = 0.04) and treatment modality (p = 0.05) were significant factors affecting financial toxicity. Conclusions: Oral cancer survivors had a poor psychosocial QOL compared to their caregivers. Treatment-related functional sequelae had a significant negative impact on quality of life across all domains. Clinical trial information: CTRI/2020/07/026848.
NFB-13. Rhabdoid Tumor Predisposition Syndrome (RTPS) – Finding Evidence by systematic Analyses
Authors: Karolina Nemes, Susanne Bens, Pascal D Johann, Mona Steinbügl, Miriam Gruhle, Denis Kachanov, Margarita Teleshova, Peter Hauser, Thorsten Simon, Stephan Tippelt, Wolfgang Eberl, Wilhelm Woessmann, Christian Kratz, Floor Abbink, Pablo Hernáiz-Driever, Matthias Eyrich, David Sumerauer, Till Milde, Harald Reinhard, Alfred Leipold, Marianne v de Wetering, Maria João Gil-da-Costa, Georg Ebetsberger-Dachs, Carmen Hernandez Marques, Nina Bauer, Veronica Biassoni, Clarice Franco Meneses, Stephanie Knirsch, Melchior Lauten, Nicolas U Gerber, Martin Chada, Kornelius Kerl, Andreas Lemmer, Boztug Heidrun, Michaela Kuhlen, Rhoikos Furtwängler, Uwe Kordes, Reiner Schneppenheim, Christian Vokuhl, Martin Hasselblatt, Thomas Kröncke, Brigitte Bison, Patrick Melchior, Beate Timmermann, Joachim Gerss, Reiner Siebert, Michael C Frühwald
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Individuals with rhabdoid tumor predisposition syndrome (RTPS1 – SMARCB1, RTPS2 – SMARCA4) have a propensity to develop malignant rhabdoid tumors (MRT). Affected patients typically present &amp;lt; age 12 months with synchronous tumors (SYN) exhibiting an unusually aggressive clinical behavior. Due to the rarity of RTPS, standards for management are evolving. METHODS: Clinical, genetic, and treatment data of 90 patients with RTPS from 16 countries were analyzed (2004 – 2020). Therapy followed the EU-RHAB recommendations. Tumors and matching blood samples were investigated for SMARCB1 and/or SMARCA4 mutations using FISH, MLPA and sequencing. DNA-methylation subgroups were determined using DNA methylation arrays. RESULTS: The median age at diagnosis of 52 girls and 38 boys was 5.5 months (0 – 203). 55.5% (50/90) of patients presented with an atypical teratoid/rhabdoid tumor (ATRT), 23.5% (21/90) demonstrated SYN, and 21% (19/90) extracranial MRT. RTPS1 was present in 84-, RTPS2 in six patients. In 77% (65/84) complete data on SMARCB1 mutational status were generated. Methylation subgroup status was available in 59% (40/68) of ATRT or SYN. The 5-year overall- (OS) and event free survival rates of patients with RTPS1 were 19.8 ± 4.8% and 15 ± 4.2%, respectively. Age &amp;lt; 1 year at diagnosis (10.1±4.3% vs. 46.7±11.1%), presence of SYN (5.3±5.1% vs. 24.8±6%), histological diagnosis (ATRT vs. eMRT/RTK/SYN) (26.8±7.1% vs. 11.9±5.6%), localized disease (34.5±8 vs. 8.3±4.6%), and presence of PGV at C-terminal (33±8.6% vs. 9.4±5.3%) were significant prognostic factors for 5-year OS in univariate analysis. INTERPRETATION: In the largest cohort of patients with RTPS, predictors significant for positive outcome could be detected: age &amp;gt; 1 year, absence of SYN, histological diagnosis ATRT, localized disease and PGV located at C-terminal. In our research project, we aim to characterize the complete pheno- and genotype of patients with RTPS to develop a risk score including surveillance recommendation.